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Developmental immunotoxicity of methylmercury: The relative sensitivity of developmental and immune parameters

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Author: Tonk, E.C.M. · Groot, D.M.G. de · Penninks, A.H. · Waalkens - Berendsen, I.D.H. · Wolterbeek, A.P.M. · Slob, W. · Piersma, A.H. · Loveren, H. van
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 2, 117, 325-335
Identifier: 409827
Keywords: Toxicology · Biomedical Research · Benchmark dose · Developmental immunotoxicity · Developmental toxicity · Dose-response modeling · Methylmercury · Perinatal exposure · Rat · gamma interferon · interleukin 10 · interleukin 13 · interleukin 2 · interleukin 4 · interleukin 6 · keyhole limpet hemocyanin · methylmercury · T lymphocyte antibody · adherent cell · animal tissue · antibody response · article · basophil · body weight · CD3+ T lymphocyte · CD4 CD8 ratio · CD8+ T lymphocyte · clinical evaluation · controlled study · cytokine production · delayed hypersensitivity · developmental screening · diagnostic value · environmental exposure · epididymis · erythrocyte · female · gestational age · immunological parameters · immunotoxicity · kidney mass · leukocyte count · litter size · liver weight · lymphocyte proliferation · natural killer cell · newborn mortality · nonhuman · rat · reticulocyte count · sensitivity and specificity · spleen cell · spleen weight · stillbirth · testis weight · thrombocyte count · thymus · weight reduction


Current developmental and reproductive toxicity protocols include only a limited set of parameters for effects on the developing immune system. In this study, a wide range of immunological parameters were included in a pre- and postnatal developmental toxicity study. Dose-response data were compared to determine the relative sensitivity of different immune and developmental parameters. Mated female Wistar rats were dosed daily by gavage with methylmercury (0, 0.1, 0.4, 0.7, 1.0, 1.5, and 2.0 mg/kg BW/day) from gestational day 6 to postnatal day (PND) 10. In addition to general, reproductive, and developmental parameters, a wide range of immunological parameters were assessed in male offspring at PNDs 21, 42, and 70. The T cell-dependent antibody response to keyhole limpet hemocyanin (KLH) was assessed following sc immunizations on PNDs 21 and 35. Dose-response data were analyzed using the benchmark dose (BMD) approach by fitting dose-response models to the various endpoints. Methylmercury induced effects on developmental parameters, such as growth parameters and pup mortality. Effects on the immune system were found at doses without observed developmental toxicity. Immune effects differed at the three time points and consisted mainly of effects on functional parameters. The parameter with the lowest 5% lower confidence bound of the BMD (BMDL) was the primary KLH-specific IgG antibody response, which showed a dose-dependent decrease with a BMD of 0.039 mg/kg BW/day (CI 0.010-0.12). These data show the relatively high sensitivity of the developing immune system and thereby illustrate the relevance of testing immune parameters in reproductive and developmental toxicity testing protocols. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.